Publications by authors named "Aaron D Viny"

30 Publications

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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss.

Sci Rep 2021 Mar 31;11(1):7288. Epub 2021 Mar 31.

Blood Research Institute, Versiti, 8727 West Watertown Plank Road, Milwaukee, WI, 53226, USA.

Acute myeloid leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes for patients. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML in adults by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the epigenetic mechanism underpinning the enhanced self-renewal conferred by cohesin-haploinsufficiency. First, given the substantial difference in the mutational spectrum between pediatric and adult AML patients, we first sought to identify if HOXA9 was also elevated in children. Next, using primary HSPCs as a model we demonstrate that abnormal self-renewal due to cohesin loss is blocked by DOT1L inhibition. In cohesin-depleted cells, DOT1L inhibition is associated with H3K79me2 depletion and a concomitant increase in H3K27me3. Importantly, we find that there are cohesin-dependent gene expression changes that promote a leukemic profile, including HoxA overexpression, that are preferentially reversed by DOT1L inhibition. Our data further characterize how cohesin mutations contribute to AML development, identifying DOT1L as a potential therapeutic target for adult and pediatric AML patients harboring cohesin mutations.
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http://dx.doi.org/10.1038/s41598-021-86646-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012605PMC
March 2021

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML.

Blood Adv 2021 Mar;5(5):1552-1564

Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.
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http://dx.doi.org/10.1182/bloodadvances.2020003734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948282PMC
March 2021

A cohesive look at leukemogenesis: The cohesin complex and other driving mutations in AML.

Neoplasia 2021 03 20;23(3):337-347. Epub 2021 Feb 20.

Blood Research Institute, Versiti, Milwaukee, WI, USA; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address:

Acute myeloid leukemia (AML) affects tens of thousands of patients a year, yet survival rates are as low as 25% in certain populations. This poor survival rate is partially due to the vast genetic diversity of the disease. Rarely do 2 patients with AML have the same mutational profile, which makes the development of targeted therapies particularly challenging. However, a set of recurrent mutations in chromatin modifiers have been identified in many patients, including mutations in the cohesin complex, which have been identified in up to 20% of cases. Interestingly, the canonical function of the cohesin complex in establishing sister chromatid cohesin during mitosis is unlikely to be the affected role in leukemogenesis. Instead, the cohesin complex's role in DNA looping and gene regulation likely facilitates disease. The epigenetic mechanisms by which cohesin complex mutations promote leukemia are not completely elucidated, but alterations of enhancer-promoter interactions and differential histone modifications have been shown to drive oncogenic gene expression changes. Such changes commonly include HoxA upregulation, which may represent a common pathway that could be therapeutically targeted. As cohesin mutations rarely occur alone, examining the impact of common co-occurring mutations, including those in NPM1, the core-binding factor complex, FLT3, and ASXL1, will yield additional insight. While further study of these mutational interactions is required, current research suggests that the use of combinatorial genetics could be the key to uncovering new targets, allowing for the treatment of AML patients based on their individual genetic profiles.
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http://dx.doi.org/10.1016/j.neo.2021.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905235PMC
March 2021

Smc3 dosage regulates B cell transit through germinal centers and restricts their malignant transformation.

Nat Immunol 2021 02 11;22(2):240-253. Epub 2021 Jan 11.

Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.

During the germinal center (GC) reaction, B cells undergo extensive redistribution of cohesin complex and three-dimensional reorganization of their genomes. Yet, the significance of cohesin and architectural programming in the humoral immune response is unknown. Herein we report that homozygous deletion of Smc3, encoding the cohesin ATPase subunit, abrogated GC formation, while, in marked contrast, Smc3 haploinsufficiency resulted in GC hyperplasia, skewing of GC polarity and impaired plasma cell (PC) differentiation. Genome-wide chromosomal conformation and transcriptional profiling revealed defects in GC B cell terminal differentiation programs controlled by the lymphoma epigenetic tumor suppressors Tet2 and Kmt2d and failure of Smc3-haploinsufficient GC B cells to switch from B cell- to PC-defining transcription factors. Smc3 haploinsufficiency preferentially impaired the connectivity of enhancer elements controlling various lymphoma tumor suppressor genes, and, accordingly, Smc3 haploinsufficiency accelerated lymphomagenesis in mice with constitutive Bcl6 expression. Collectively, our data indicate a dose-dependent function for cohesin in humoral immunity to facilitate the B cell to PC phenotypic switch while restricting malignant transformation.
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http://dx.doi.org/10.1038/s41590-020-00827-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855695PMC
February 2021

Single-cell mutation analysis of clonal evolution in myeloid malignancies.

Nature 2020 11 28;587(7834):477-482. Epub 2020 Oct 28.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later. Although bulk sequencing can provide information about leukaemia biology and prognosis, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate the order of mutations. To delineate the clonal framework of myeloid malignancies, we performed single-cell mutational profiling on 146 samples from 123 patients. Here we show that AML is dominated by a small number of clones, which frequently harbour co-occurring mutations in epigenetic regulators. Conversely, mutations in signalling genes often occur more than once in distinct subclones, consistent with increasing clonal diversity. We mapped clonal trajectories for each sample and uncovered combinations of mutations that synergized to promote clonal expansion and dominance. Finally, we combined protein expression with mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our findings provide insights into the pathogenesis of myeloid transformation and how clonal complexity evolves with disease progression.
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http://dx.doi.org/10.1038/s41586-020-2864-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677169PMC
November 2020

PRMT5 Inhibition Modulates E2F1 Methylation and Gene-Regulatory Networks Leading to Therapeutic Efficacy in JAK2-Mutant MPN.

Cancer Discov 2020 Nov 15;10(11):1742-1757. Epub 2020 Jul 15.

Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

We investigated the role of PRMT5 in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key PRMT5 targets contributing to MPN maintenance. PRMT5 is overexpressed in primary MPN cells, and PRMT5 inhibition potently reduced MPN cell proliferation . PRMT5 inhibition was efficacious at reversing elevated hematocrit, leukocytosis, and splenomegaly in a model of JAK2 polycythemia vera and leukocyte and platelet counts, hepatosplenomegaly, and fibrosis in the MPL model of myelofibrosis. Dual targeting of JAK and PRMT5 was superior to JAK or PRMT5 inhibitor monotherapy, further decreasing elevated counts and extramedullary hematopoiesis PRMT5 inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell-cycle arrest, and increased apoptosis. Our data link PRMT5 to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of PRMT5 inhibitors in MPN. SIGNIFICANCE: Expression of PRMT5 and E2F targets is increased in JAK2 MPN. Pharmacologic inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2/MPL MPN models and primary samples. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642059PMC
November 2020

Drug modulation by nuclear condensates.

Science 2020 06;368(6497):1314-1315

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1126/science.abc5318DOI Listing
June 2020

DNA methylation disruption reshapes the hematopoietic differentiation landscape.

Nat Genet 2020 04 23;52(4):378-387. Epub 2020 Mar 23.

New York Genome Center, New York, NY, USA.

Mutations in genes involved in DNA methylation (DNAme; for example, TET2 and DNMT3A) are frequently observed in hematological malignancies and clonal hematopoiesis. Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid versus myelomonocytic progenitors following Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells. To reconcile genome-wide DNAme changes with specific erythroid versus myelomonocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A-mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the topography of hematopoietic differentiation, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in CpG enrichment of the transcription factor binding motif.
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http://dx.doi.org/10.1038/s41588-020-0595-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216752PMC
April 2020

Driver mutations in acute myeloid leukemia.

Curr Opin Hematol 2020 Mar;27(2):49-57

Human Oncology and Pathogenesis Program.

Purpose Of Review: The mutational landscape of acute myeloid leukemia (AML) has revised diagnostic, prognostic, and therapeutic schemata over the past decade. Recurrently mutated AML genes have functional consequences beyond typical oncogene-driven growth and loss of tumor suppresser function.

Recent Findings: Large-scale genomic sequencing efforts have mapped the complexity of AML and trials of mutation-based targeted therapy has led to several FDA-approved drugs for mutant-specific AML. However, many recurrent mutations have been identified across a spectrum from clonal hematopoiesis to myelodysplasia to overt AML, such as effectors of DNA methylation, chromatin modifiers, and spliceosomal machinery. The functional effects of these mutations are the basis for substantial discovery.

Summary: Understanding the molecular and pathophysiologic functions of key genes that exert leukemogenic potential is essential towards translating these findings into better treatment for AML.
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http://dx.doi.org/10.1097/MOH.0000000000000567DOI Listing
March 2020

Stability and uniqueness of clonal immunoglobulin CDR3 sequences for MRD tracking in multiple myeloma.

Am J Hematol 2019 12 21;94(12):1364-1373. Epub 2019 Oct 21.

Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, New York.

Minimal residual disease (MRD) tracking, by next generation sequencing of immunoglobulin sequences, is moving towards clinical implementation in multiple myeloma. However, there is only sparse information available to address whether clonal sequences remain stable for tracking over time, and to what extent light chain sequences are sufficiently unique for tracking. Here, we analyzed immunoglobulin repertoires from 905 plasma cell myeloma and healthy control samples, focusing on the third complementarity determining region (CDR3). Clonal heavy and/or light chain expression was identified in all patients at baseline, with one or more subclones related to the main clone in 3.2%. In 45 patients with 101 sequential samples, the dominant clonal CDR3 sequences remained identical over time, despite differential clonal evolution by whole exome sequencing in 49% of patients. The low frequency of subclonal CDR3 variants, and absence of evolution over time in active multiple myeloma, indicates that tumor cells at this stage are not under selective pressure to undergo antibody affinity maturation. Next, we establish somatic hypermutation and non-templated insertions as the most important determinants of light chain clonal uniqueness, identifying a potentially trackable sequence in the majority of patients. Taken together, we show that dominant clonal sequences identified at baseline are reliable biomarkers for long-term tracking of the malignant clone, including both IGH and the majority of light chain clones.
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http://dx.doi.org/10.1002/ajh.25641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449571PMC
December 2019

Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation.

Cell Stem Cell 2019 11 5;25(5):682-696.e8. Epub 2019 Sep 5.

Human Oncology and Pathogenesis Program and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.
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http://dx.doi.org/10.1016/j.stem.2019.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842438PMC
November 2019

Loss of plasmacytoid dendritic cell differentiation is highly predictive for post-induction measurable residual disease and inferior outcomes in acute myeloid leukemia.

Haematologica 2019 07 6;104(7):1378-1387. Epub 2018 Dec 6.

Department of Pathology, Hematopathology Diagnostic Service

Measurable residual disease is associated with inferior outcomes in patients with acute myeloid leukemia (AML). Measurable residual disease monitoring enhances risk stratification and may guide therapeutic intervention. The European LeukemiaNet working party recently came to a consensus recommendation incorporating leukemia associated immunophenotype-based different from normal approach by multi-color flow cytometry for measurable residual disease evaluation. However, the analytical approach is highly expertise-dependent and difficult to standardize. Here we demonstrate that loss of plasmacytoid dendritic cell differentiation after 7+3 induction in AML is highly specific for measurable residual disease positivity (specificity 97.4%) in a uniformly treated patient cohort. Moreover, loss of plasmacytoid dendritic cell differentiation as determined by a blast-to-plasmacytoid dendritic cell ratio >10 was strongly associated with inferior overall and relapse-free survival (RFS) [Hazard ratio 2.79, 95% confidence interval (95%CI): 0.98-7.97; =0.077) and 3.83 (95%CI: 1.51-9.74; =0.007), respectively), which is similar in magnitude to measurable residual disease positivity. Importantly, measurable residual disease positive patients who reconstituted plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) showed a higher rate of measurable residual disease clearance at later pre-transplant time points compared to patients with loss of plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) (6 of 12, 50% 2 of 18, 11%; =0.03). Furthermore pre-transplant plasmacytoid dendritic cell recovery was associated with superior outcome in measurable residual disease positive patients. Our study provides a novel, simple, broadly applicable, and quantitative multi-color flow cytometry approach to risk stratification in AML.
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http://dx.doi.org/10.3324/haematol.2018.203018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601104PMC
July 2019

A Case of Familial Mediterranean Fever with Extensive Lymphadenopathy and Complex Heterozygous Genotype Presenting in the Fourth Decade.

Case Rep Rheumatol 2018 1;2018:9670801. Epub 2018 Apr 1.

Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Familial Mediterranean fever (FMF) is an inherited disease caused by loss of function mutations in the gene encoding pyrin, a negative regulator of interleukin-1. The disease is characterized by recurrent fever and self-limited attacks of joint, chest, and abdominal pain but lymphadenopathy is an infrequent manifestation. While mesenteric lymphadenopathy has been described in several cases in the literature; hilar, paratracheal, axillary, pelvic, and retroperitoneal lymphadenopathy are extremely rare and have been reported separately in very few individuals. In this report, we present a patient with late-onset FMF with extensive lymphadenopathy in all of the aforementioned anatomic regions. Genetic analysis identified three heterozygous pyrin mutations in a patient with no affected family members. Genetic investigation of the patient's mother identified a novel carrier haplotype E148Q/P369S. The proband also inherited the previously described and rare A744S mutation previously not thought to be a disease-defining lesion. This unique compound heterozygous genotype resulted in a novel genotype-phenotype association producing an atypical clinical presentation of FMF that fits within the pattern of several case reports of late-onset disease with respect to clinical course and therapeutic response.
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http://dx.doi.org/10.1155/2018/9670801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901998PMC
April 2018

Cohesin mutations in myeloid malignancies made simple.

Curr Opin Hematol 2018 03;25(2):61-66

Human Oncology & Pathogenesis Program, Center for Hematologic Malignancies, and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.

Purpose Of Review: Recurrent loss of function mutations within genes of the cohesin complex have been identified in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). STAG2 is the most commonly mutated cohesin member in AML as well as solid tumors. STAG2 is recurrently, mutated in Ewing's Sarcoma, bladder cancer, and glioblastoma, and is one of only ten genes known to be recurrently mutated in over four distinct tissue types of human cancer RECENT FINDINGS: The cohesin complex, a multiprotein ring, is canonically known to align and stabilize replicated chromosomes prior to cell division. Although initially thought to lead to unequal chromosomal separation in dividing cells, data in myeloid malignancies show this is not observed in cohesin mutant MDS/AML, either in large patient cohorts or mouse models. Mounting evidence supports a potential alternate mechanism whereby drivers of cell-type specific gene expression and hematopoietic development are impaired through alteration in three-dimensional nuclear organization and gene structure.

Summary: Understanding the functional consequences of cohesin mutations in regulating lineage-specific and signal-dependent defects and in myeloid transformation will identify novel pathophysiologic mechanisms of disease and inform the development of novel therapeutic targets.
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http://dx.doi.org/10.1097/MOH.0000000000000405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601335PMC
March 2018

Racial disparities in the survival of American children, adolescents, and young adults with acute lymphoblastic leukemia, acute myelogenous leukemia, and Hodgkin lymphoma.

Cancer 2016 Sep 10;122(17):2723-30. Epub 2016 Jun 10.

Human Oncology & Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Race-based survival in children and adolescents with hematologic malignancies has been a national challenge for decades. Large-scale investigations of age- and race-based survival trends over time in these patients have not previously been reported. The objective of this study was to investigate whether race- and age-related differences in pediatric and adolescent and young adult (AYA) leukemia and lymphoma survival persist and to what extent these differences have changed over time.

Methods: Using the Surveillance, Epidemiology, and End Results program, this study investigated the outcomes of black and white (1975-2012; n = 27,369) and white and Hispanic (1992-2012; n = 20,574) children (0-14 years old) and AYAs (15-39 years old) with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and Hodgkin lymphoma (HL). Estimates of 5- and 10-year relative survival were compared over time.

Results: Trends showed a convergence of survival for white and black children with ALL but a divergence in survival for AYA patients. Hispanic children and AYAs both suffered inferior outcomes. Trends for AML revealed persistent survival differences between black and white children and suggested worsening disparities for AYAs. Survival trends in HL revealed sustained survival differences between black and white AYA patients, whereas no differences were found in Hispanic and white patient outcomes for AML or HL.

Conclusions: Although survival for children and AYAs with ALL, AML, and HL has improved over the past 4 decades, differences persist between black, white, and Hispanic children and AYAs; survival disparities between black and white children with ALL have been nearly eliminated. Strategies aimed at identifying causality and reducing disparities are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2723-2730. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992431PMC
September 2016

Roads Diverge--A Robert Frost View of Leukemia Development.

N Engl J Med 2016 Jun;374(23):2282-4

From the Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.

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http://dx.doi.org/10.1056/NEJMe1603420DOI Listing
June 2016

A Multiplexed System for Quantitative Comparisons of Chromatin Landscapes.

Mol Cell 2016 Jan 10;61(1):170-80. Epub 2015 Dec 10.

Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address:

Genome-wide profiling of histone modifications can provide systematic insight into the regulatory elements and programs engaged in a given cell type. However, conventional chromatin immunoprecipitation and sequencing (ChIP-seq) does not capture quantitative information on histone modification levels, requires large amounts of starting material, and involves tedious processing of each individual sample. Here, we address these limitations with a technology that leverages DNA barcoding to profile chromatin quantitatively and in multiplexed format. We concurrently map relative levels of multiple histone modifications across multiple samples, each comprising as few as a thousand cells. We demonstrate the technology by monitoring dynamic changes following inhibition of p300, EZH2, or KDM5, by linking altered epigenetic landscapes to chromatin regulator mutations, and by mapping active and repressive marks in purified human hematopoietic stem cells. Hence, this technology enables quantitative studies of chromatin state dynamics across rare cell types, genotypes, environmental conditions, and drug treatments.
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http://dx.doi.org/10.1016/j.molcel.2015.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707994PMC
January 2016

"This is not me": patient, family, cultural and clinician considerations in cases of severe cancer-related debility.

J Gastrointest Oncol 2015 Oct;6(5):589-93

1 Memorial Sloan Kettering Cancer Center, New York, NY, USA ; 2 Weill Cornell Medical College, New York, NY, USA ; 3 American University of Beirut, Beirut, Lebanon ; 4 National Guard Hospital at King Abdul-Aziz Medical City, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.3978/j.issn.2078-6891.2015.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570910PMC
October 2015

Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis.

J Exp Med 2015 Oct 5;212(11):1819-32. Epub 2015 Oct 5.

Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Department of Pathology, Molecular Cytology Core Facility, and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065

Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation; however, cohesin mutant leukemias do not show genomic instability. We hypothesized that reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo, including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose dependency for cohesin in regulating chromatin structure and HSC function.
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http://dx.doi.org/10.1084/jem.20151317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612085PMC
October 2015

Genetic alterations of the cohesin complex genes in myeloid malignancies.

Blood 2014 Sep 8;124(11):1790-8. Epub 2014 Jul 8.

Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;

Somatic cohesin mutations have been reported in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To account for the morphologic and cytogenetic diversity of these neoplasms, a well-annotated cohort of 1060 patients with myeloid malignancies including MDS (n = 386), myeloproliferative neoplasms (MPNs) (n = 55), MDS/MPNs (n = 169), and AML (n = 450) were analyzed for cohesin gene mutational status, gene expression, and therapeutic and survival outcomes. Somatic cohesin defects were detected in 12% of patients with myeloid malignancies, whereas low expression of these genes was present in an additional 15% of patients. Mutations of cohesin genes were mutually exclusive and mostly resulted in predicted loss of function. Patients with low cohesin gene expression showed similar expression signatures as those with somatic cohesin mutations. Cross-sectional deep-sequencing analysis for clonal hierarchy demonstrated STAG2, SMC3, and RAD21 mutations to be ancestral in 18%, 18%, and 47% of cases, respectively, and each expanded to clonal dominance concordant with disease transformation. Cohesin mutations were significantly associated with RUNX1, Ras-family oncogenes, and BCOR and ASXL1 mutations and were most prevalent in high-risk MDS and secondary AML. Cohesin defects were associated with poor overall survival (27.2 vs 40 months; P = .023), especially in STAG2 mutant MDS patients surviving >12 months (median survival 35 vs 50 months; P = .017).
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http://dx.doi.org/10.1182/blood-2014-04-567057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162108PMC
September 2014

High rate of both hematopoietic and solid tumors associated with large granular lymphocyte leukemia.

Leuk Lymphoma 2015 Feb 17;56(2):503-4. Epub 2014 Jul 17.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center , New York, NY , USA.

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http://dx.doi.org/10.3109/10428194.2014.927459DOI Listing
February 2015

Genetics of myeloproliferative neoplasms.

Cancer J 2014 Jan-Feb;20(1):61-5

From the Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY.

In the last decade, genomic studies have identified multiple recurrent somatic mutations in myeloproliferative neoplasms (MPNs). Beginning with the discovery of the JAK2 V617F mutation, multiple additional mutations have been found that constitutively activate cell-signaling pathways, including MPL, CBL, and LNK. Furthermore, several classes of epigenetic modifiers have also been identified, in patients with MPN, revealing a requirement for mutations in other pathways to cooperate with JAK-STAT pathway mutations in MPN pathogenesis. Mutations in the de novo DNA methylation protein, DNMT3A, demethylation machinery, TET2 and related IDH1/2 production of oncometabolite 2-hydroxygluterate, and polycomb complex proteins EZH2 and ASXL1 have opened new pathophysiologic clues into these diseases. The prognostic relevance of these novel disease alleles remains an important area of investigation, and clinical trials are currently underway to determine if these findings represent tractable therapeutic targets, either alone, or in combination with JAK2 inhibition.
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http://dx.doi.org/10.1097/PPO.0000000000000013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898518PMC
May 2015

Hemorrhagic complications associated with dabigatran use.

Clin Toxicol (Phila) 2012 Nov 12;50(9):854-7. Epub 2012 Sep 12.

New York City Poison Control Center, Bellevue Hospital Center, New York University, New York, NY 10016, USA.

Objective: Dabigatran is a direct thrombin inhibitor approved for anticoagulation in non-valvular atrial fibrillation and, in some countries, for thromboembolism prophylaxis following select orthopedic surgeries. Despite decreased rates of thromboembolism, bleeding remains a risk due to the inability to conveniently monitor anticoagulant effect and the lack of a reversal agent.

Case Series: We present four cases of dabigatran-related bleeding. A 79-year-old man on aspirin, clopidogrel, and dabigatran presented with rectal bleeding and epistaxis. He died despite transfusion and administration of prothrombin complex concentrate. A 73-year-old woman on dabigatran and aspirin survived after transfusion and an emergent sternotomy for cardiac tamponade. An 86 year-old man with kidney disease and thrombocytopenia received packed red blood cells, platelets, and fresh frozen plasma for rectal bleeding while on dabigatran. An 80 year-old man on dabigatran had a subdural hematoma after falling and hitting his head. Serial imaging showed no progression.

Conclusion: The absence of a reversal agent for dabigatran raises concern for uncontrollable bleeding and death. Dabigatran's listed contraindications include active bleeding and a history of dabigatran hypersensitivity reaction. Wider use may result in bleeding rates higher than anticipated from clinical trials. Risks factors that may have contributed to bleeding in these patients include concomitant bleeding diathesis, antiplatelet agent use, renal insufficiency, advanced age, and fall risks.
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http://dx.doi.org/10.3109/15563650.2012.721888DOI Listing
November 2012

Clonal drift demonstrates unexpected dynamics of the T-cell repertoire in T-large granular lymphocyte leukemia.

Blood 2011 Oct 24;118(16):4384-93. Epub 2011 Aug 24.

Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

T-cell large granular lymphocyte leukemia (T-LGLL) is characterized by chronic lymphoproliferation of cytotoxic T lymphocytes (CTLs) and is associated with lineage-restricted cytopenias. Introduction of T-cell receptor (TCR) variable β-chain (Vβ) monoclonal antibodies has facilitated identification and enumeration of clonal CTLs by flow cytometry. A highly skewed TCR Vβ repertoire identified by flow cytometry is strongly associated with monoclonal CDR3 regions by quantitative sequencing and positive TCRγ rearrangement assays. Therefore, Vβ expansions can serve as surrogate markers of CTL clonality to assess clonal kinetics in T-LGLL. We analyzed the TCR repertoire in 143 patients, 71 of which were available for serial measurements over 6 to 96 months. Although the majority (38/71, 54%) maintained a consistent monoclonal expansion, many (26/71, 37%) unexpectedly displayed a change in the dominant clone, whereby the original CTL clone contracted and another emerged as demonstrated by Vβ typing. Our results demonstrate that the T-cell repertoire is more dynamic in T-LGLL than recognized previously, illustrating the heterogeneity of disorders under this categorization.
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http://dx.doi.org/10.1182/blood-2011-02-338517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204910PMC
October 2011

MICA polymorphism identified by whole genome array associated with NKG2D-mediated cytotoxicity in T-cell large granular lymphocyte leukemia.

Haematologica 2010 Oct 11;95(10):1713-21. Epub 2010 May 11.

Department of Translational Hematologic and Oncologic Research, Taussig Cancer Center R/40, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, USA.

Background: Large granular lymphocyte leukemia is a semi-autonomous clonal proliferation of cytotoxic T cells accompanied by immune cytopenias and various autoimmune conditions. Due to the rarity of this disease and its association with autoimmune diseases, a theoretical germline or somatic mutation might have significant penetrance, thus enabling detection, even from samples of suboptimal size, through genome-wide association studies.

Design And Methods: To investigate a non-mendelian genetic predisposition to large granular lymphocyte leukemia, we used a step-wise method for gene discovery. First, a modified 'random forests' technique was used for candidate gene identification: this was followed by traditional allele-specific polymerase chain reaction, sequencing modalities, and mechanistic assays.

Results: Our analysis found an association with MICA, a non-peptide-presenting, tightly regulated, stress-induced MHC-like molecule and cognate receptor for NKG2D, found abundantly on large granular lymphocyte leukemia cells. Sequencing of germline DNA revealed a higher frequency of MICA*00801/A5.1 in patients with large granular lymphocyte leukemia than in matched controls (64% versus 41%, P<0.001, homozygous 40% versus 15%, P<0.001). Flow cytometry was employed to determine the expression of MICA within hematologic compartments, showing that the signal intensity of MICA was increased in granulocytes from neutropenic patients with large granular lymphocyte leukemia in comparison with that in controls (P=0.033). Furthermore, neutrophil counts were inversely correlated with MICA expression (R(2)=0.50, P=0.035). Finally, large granular lymphocyte leukemia cells were able to selectively kill MICA(+) Ba/F3 lymphocytes transfected with human MICA*019 in a dose-dependent manner compared to naïve cells (P<0.001), an effect mitigated by administration of an anti-NKG2D antibody (P=0.033).

Conclusions: Our results illustrate that MICA-NKG2D played a role in disease pathogenesis in the majority of patients in our cohort of cases of large granular lymphocyte leukemia and further investigation into this signaling axis may provide potent therapeutic targets.
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http://dx.doi.org/10.3324/haematol.2010.021865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948097PMC
October 2010

Outcomes of splenectomy in T-cell large granular lymphocyte leukemia with splenomegaly and cytopenia.

Exp Hematol 2008 Sep 11;36(9):1078-83. Epub 2008 Jun 11.

Experimental Hematology and Hematopoiesis Section, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Objective: T-cell large granular lymphocyte leukemia (T-LGL) is a chronic clonal lymphoproliferation of cytotoxic T cells often complicated by cytopenia. Because the outcomes of splenectomy in patients with T-LGL have been only reported sporadically, we objectively assessed the outcomes of splenectomy.

Materials And Methods: When a cohort of 56 T-LGL patients was analyzed, patients with splenomegaly (n = 34) and had higher frequency of bi- and pancytopenia than patients with no splenomegaly (70% vs 27%; p = 0.001). We identified 15 patients who, in their clinical course, underwent splenectomy and studied their hematological and clinical outcomes.

Results: Indications for splenectomy included symptomatic splenomegaly and/or severe refractory cytopenia. Median spleen weight was 1300 g, consistent with diagnosis of splenomegaly; T-cell receptor (TCR)-gamma rearrangement and typical T-LGL were detected by immunophenotype in all specimens. There was no surgery-related mortality, with the median follow-up and survival of 719 and 498 days, respectively. Two patients died due to causes possibly related to the splenectomized state and/or primary disease. All patients showed lineage-specific hematologic response and achieved transfusion independence; however, precise molecular analysis of TCR and variable chain Vbeta flow cytometry showed persistence of the LGL clones.

Conclusion: We conclude that splenectomy constitutes a viable and safe therapeutic option for patients with T-LGL, splenomegaly, and refractory cytopenia.
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http://dx.doi.org/10.1016/j.exphem.2008.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537502PMC
September 2008

Chronic B-cell dyscrasias are an important clinical feature of T-LGL leukemia.

Leuk Lymphoma 2008 May;49(5):932-8

Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.

T cell large granular lymphocyte leukemia (T-LGL) is characterised by semiautonomous proliferation of monoclonal cytotoxic T lymphocytes, which can result in neutropenia, splenomegaly, and is associated with various autoimmune disorders, particularly rheumatoid arthritis. The coexistence of T-LGL leukemia with B cell abnormalities has previously been identified in case reports. However, no systematic analysis to determine the frequency of this co-association has been reported. Analysis of 63 T-LGL patients revealed a frequent association with humoral immune system abnormalities. We identified coexisting B cell dyscrasias in 17 T-LGL patients (27% of total), of whom 12 had monoclonal gammopathy of unknown significance (MGUS) (19%), and 5 had chronic lymphocytic leukemia (CLL) (8%). The presence of both MGUS and CLL was found in 2 patients (3%) and follicular lymphoma was identified with MGUS in another T-LGL patient (2%). Additionally, polyclonal hypergammaglobulinemia or hypogammaglobulinemia was found in 10 additional LGL leukemia patients bringing the total frequency of B cell abnormalities in T-LGL leukemia to 43% in our cohort. The co-association of B cell pathology with T-LGL suggests that either a common antigen drives clonal B and T cells, or that humoral malignancy could serve as the stimulus for lymphocyte expansion representing an overactive anti-tumour surveillance.
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http://dx.doi.org/10.1080/10428190801932635DOI Listing
May 2008